The influence of the schedule and the dose of gemcitabine on the anti-tumour efficacy in experimental human cancer

Abstract

The therapeutic efficacy of gemcitabine, a new nucleoside analogue, was assessed in a variety of well-established human soft tissue sarcoma and ovarian cancer xenografts grown s.c. in nude mice. Tumour lines selected had different histological subtypes, growth rates and sensitivities to conventional cytostatic agents. The three different doses and schedules designed on the basis of a mean weight loss between 5% and 15% were i.p. injections of daily 3.5 mg kg-1 x 4, every 3 days 120 mg kg-1 x 4, and weekly 240 mg kg-1 x 2, which ultimately resulted in 19%, 10% and 4% toxic deaths, respectively. The weekly schedule induced > or = 50% growth inhibition in 2/4 soft tissue sarcoma and 4/6 ovarian cancer lines, while in three ovarian cancer lines > or = 75% growth inhibition was obtained. The anti-tumour effects of gemcitabine appeared to be similar or even better than previous data with conventional drugs tested in the same tumour lines. In comparison with the every 3 days schedule, the weekly and the daily schedule were less effective in 5/7 and 3/3 tumour lines (P < 0.001), respectively. In another experiment in three human tumour lines selected for their differential sensitivity to gemcitabine, weekly injections of 240 mg kg-1 x 6 did not result in a significant increase in the percentages of growth inhibition when compared to lower doses of 120 mg kg-1 or 60 mg kg-1 in the same schedule. However, the 240 mg kg-1 weekly x 6 schedule showed superior effects in 2/3 tumour lines in comparison with the same dose given every 2 weeks x 3 (P < 0.05). The preclinical activity of gemcitabine suggests that the drug can induce responses in soft tissue sarcoma and ovarian cancer patients. Our results further indicate that clinical trials of gemcitabine in solid tumour types should be designed on the basis of a schedule rather than a dose dependence.

Metronomic chemotherapy regimens in oncology

“…У животных наиболее применима метрономная доза препарата 1 мг / кг / сут, для клинических исследований дозы ва-рьируют, и не существует рекомендуемой метроном-ной дозировки [77,78]. Гемцитабин активен в отноше-нии аденокарцином молочной железы, поджелудоч-ной железы, легкого, толстой кишки, яичников, а также сарком [78][79][80].…”

Prolonged Versus Standard Gemcitabine Infusion: Translation of Molecular Pharmacology to New Treatment Strategy

“…This FDR approach was derived from earlier studies on cytarabine that showed a greater area under the concentration-time curve (AUC) of cytarabine triphosphate (ara-CTP), the active metabolite of cytarabine, in leukemic cells of patients following prolonged infusion times of cytarabine [11,12]. The activity and toxicity of gemcitabine depend on the dose and dosing schedule [13,14]. In various randomized clinical trials, FDR administration was compared with the standard 30-minute infusion of gemcitabine.…”

Gemcitabine following radiotherapy with concurrent 5‐fluorouracil for nonmetastatic adenocarcinoma of the pancreas

“…Gemcitabine (2Ј,2Ј-difluorodeoxycytidine, dFdC) is a novel fluorine-substituted cytarabine (Ara-C) analog with demonstrated antitumor activity against a broad spectrum of murine experimental tumor models and human tumor xenografts [14][15][16]. The US Food and Drug Administration recently approved gemcitabine for use in pancreatic cancer based on studies of this drug in patients with advanced or metastatic disease [17][18][19][20].…”